Aviilx_long is a groundbreaking formulation to specifically target the Multiorgan system effects of COVID-19. Multiorgan system effects of COVID-19 have been documented in most, if not all, body systems including cardiovascular, pulmonary, renal, dermatologic, neurologic, and psychiatric.
Multisystem inflammatory syndrome (MIS) and autoimmune conditions can also occur after COVID-19. Aviilx_long contains standardized botanical compounds that have been found to inhibit the effects of SARS-CoV-2 through multiple pathways including: anti-inflammatory, anti-viral and protecting against tissue and cell damage.
2 capsules twice a day.
Multiorgan system effects of COVID-19 have been documented in most, if not all, body systems including cardiovascular, pulmonary, renal, dermatologic, neurologic, and psychiatric. Multisystem inflammatory syndrome (MIS) can occur after COVID-19, leading
to long-term symptoms due to unresolved complications. It is unknown how long these multiorgan system effects may last.
A comprehensive review of adverse postCOVID health outcomes and potential longCOVID effects observed adverse outcomes affected many bodily systems, including (i) immune system (e.g., Guillain-Barré syndrome, rheumatoid arthritis, pediatric inflammatory multisystem syndromes such as Kawasaki disease), (ii) hematological system (vascular hemostasis, blood coagulation),
(iii) pulmonary system (respiratory failure, pulmonary thromboembolism, pulmonary embolism, pneumonia, pulmonary vascular damage, pulmonary fibrosis), (iv) cardiovascular system (myocardial hypertrophy, coronary artery atherosclerosis, focal myocardial fibrosis, acute myocardial infarction, cardiac hypertrophy), (v) gastrointestinal,
hepatic, and renal systems (diarrhea, nausea/vomiting, abdominal pain, anorexia, acid reflux, gastrointestinal hemorrhage, lack of appetite/constipation), (vi) skeletomuscular system (immune-mediated skin diseases, psoriasis, lupus), (vii) nervous system (loss of
taste/smell/hearing, headaches, spasms, convulsions, confusion, visual impairment, nerve pain, dizziness, impaired consciousness, nausea/vomiting, hemiplegia, ataxia, stroke, cerebral hemorrhage)(viii) mental health (stress, depression and anxiety).
Long COVID is marked by an increased secretion of pro-inflammatory cytokines and chemokines, like interleukins (IL-1, IL-6, IL8, IL-12, and IL-120), tumour necrosis factors (TNF-a, IFN-B and IFN-), CX-C motif chemokine ligand 10 (CXCL10), macrophage inflammatory protein-1a (MIP-1a), monocyte chemo-attractant protein-1 (MCP-1) and in-
terferon gamma-induced protein 10 (IP-10). Peripheral inflammation caused by COVID-19 may have long-term consequences in those that recover, leading to chronic medical conditions such as dementia and neurodegenerative disease, likely through neuroinflammatory mechanisms that can be compounded by an unhealthy diet.
30-40% of COVID-19 survivors have shown the symptoms of anxiety, depression, sleep disturbances, and post-traumatic stress disorder. In a large-scale analysis of nearly 60,000 COVID-19 survivors within 90 d after COVID-19 diagnosis, it was estimated that the probability of occurrence of new psychiatric illnesses was 5.8% constituting predominantly anxiety disorder (4.7%), mood disorder (2%), insomnia (1.9%), dementia (1.6%).
Saini and Aneja (2021) propose that long COVID-19 may predispose recovered patients to cancer development and accelerate cancer progression. This hypothesis is based
on growing evidence of the ability of SARSCoV-2 to modulate oncogenic pathways, promote chronic low-grade inflammation, and cause tissue damage.
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Tenuigenin, a major active component of Polygala tenuifolia, has been shown to have potential antiinflammatory activity, but the underlying mechanisms remain obscure. Fan et al., (2017) explored the effect of tenuigenin on dopaminergic neurons in substantia nigra. They activated pyrin domaincontaining 3 (NLRP3) inflammasome in both BV2 microglia cells and adult mice to investigate the mechanisms for the neuroprotective effect of tenuigenin. They further found that tenuigenin reduced intracellular reactive oxygen species (ROS) production and suppressed NLRP3 inflammasome activation, subsequent caspase-1
cleavage, and interleukin-1B secretion in BV2 microglia cells. These data indicate that tenuigenin inhibits the activation of NLRP3 inflammasome via downregulating ROS. Findings reveal that tenuigenin protects dopaminergic neurons.
Findings by Chen et al., (2012) showed that addition of tenuigenin to the neural stem cell medium increased the number of newly formed neurospheres. More neurons were also obtained when tenuigenin was added in the differentiation medium. These findings suggest that tenuigenin is involved in regulating the proliferation and differentiation of hippocampal neural stem cells. This result may be one of the underlying reasons for tenuigenin’s nootropic and anti-aging effects.
Tenuigenin decreased the elevated reactive oxygen species induced by methylglyoxal. In addition, tenuigenin inhibited activation of caspase-3 and reversed down-regulation of the ratio of Bcl-2/Bax, both of which were induced by methylglyoxal stimulation. The results suggest that tenuigenin displays antiapoptotic and antioxidative activity in hippocampal neurons due to scavenging
of intracellular reactive oxygen species, regulating Bcl-2 family and suppressing caspase-3 activity.
Anxiety/ HPA axis. This study demonstrated that the administration of Polygala tenuifolia prior to repeated restraint stress significantly reduced anxiety-like behaviours.
These changes were associated with a modification of the central noradrenergic system and the upregulation of BDNF expression, which in turn attenuated activity in the HPA axis.
The metabolism of polydatin, geniposide, quercitrin and glycyrrhizin was significantly inhibited by one or several anti-coronavirus drugs of 100 ?M around 1 h and 4 h. Both baicalin (BA) and jasminoidin (JA) are active ingredients in Chinese herb medicine Scutellaria baicalensis and Fructus gardeniae, respectively. They have been shown to exert additive neuroprotective action.
The specific mechanisms of BA and JA were associated with apoptosis and cancer-relat-
ed signalling and endocrine and hormone regulation, respectively. In the BJ group, novel target profiles distinct from monotherapies were revealed, including 11 specific target molecules, 10 functions, and 10 pathways, the majority of which were related
to a virus-mediated immune response. The pure additive effects between BA and JA were based on enhanced action in virus-mediated immune response. In a study by Hu et al, (2019) fractionation of gardenia prior to further in vivo investigation has for the first time provided reasonable explanation for the anti-inflammatory activity of this herbal remedy. Their study showed that extracts from gardenia have anti-inflammatory properties. Taken together, this maiden attempt demonstrated that TIG (mainly geniposide) is more important in evaluating the anti-inflammatory activity of G. jasminoides Ellis.
Alzheimer’s disease (AD) is highly correlated with neuroinflammation and oxidative stress in brain causing neuronal loss. Nuclear factor of activated B-cells (NF-B) is involved in physiological inflammatory processes and thus representing a promising target for inflammation-based AD therapy. Phytochemicals can interfere with the NFB pathway. They inhibit the phosphorylation or the ubiquitination of signalling molecules, and thus, inhibit the degradation of IB. Tanshinone IIA, artemisinin, and paeoniflorin were described as promising NF-B inhibitors.
One important feature of COVID-19 pathophysiology is the activation of immune cells, with consequent massive production and release of inflammatory mediators that may cause impairment of several organ functions, including the brain. In addition to its classical role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) has immunomodulatory properties, downregu-
lating the inflammatory response by central and peripheral mechanisms.
The presence of angiotensin-converting enzyme 2 (ACE2) receptors may not be the only explanation of central nervous system tropism. There is evidence that axonal transport (through nerve fibers) may be responsible for spreading the virus. COVID-19 may cause cytokine storm syndrome which, together with an increase in Ddimer levels, low platelet levels, and hypoxia (inadequate oxygen supply), raises the risk of cerebrovascular events. Dietary fatty acids affecting the pro-inflammatory cytokines have been suggested to affect the metabolic fate of Tryptophan (Trp). TRP and its metabolites including melatonin have the capacity to improve the immune system and reduce inflammation in various conditions. Trp and its metabolites are known to be beneficial in improving the function of the immune sys
Gardinassi et al, (2020) revealed a high involvement of inflammatory networks and increased expression of genes involved in tryptophan metabolism in COVID19 patients. There is a definite involvement of IL-6 in the immune response in COVID-19 and IL-6 is thought to affect tryptophan catabolism in other pathophysiological conditions.
SARS-CoV papain-like protease (PLpro) inhibitors have been reported from many synthetic peptidyl compound libraries, but little natural compounds have been shown to exhibit PLpro inhibition. The natural-derived inhibitors include diarylheptanoids, tanshinones, flavonoids and cinnamic amides. The detailed protein-inhibitor mechanistic analysis of these species indicated that the chalcones exhibited competitive inhibition characteristics to the SARS-CoV 3CLpro. An ethanol extract of Angelica keiskei, a polyphenol, showed significant inhibition against 3CLpro as it contains bioactive chalcones, flavanones and coumarins that exhibit antioxidant, antidiabetic, antihypertensive and cancer chemopreventive effects.
Additionally, our group has succeeded in isolating and characterizing influenza virus neuraminidase inhibitors from this plant. Chalcones are natural open chain flavonoids that are found in various plants and can be synthesized in labs. Several studies have shown that these small organic molecules exert several pharmacological activities, including antiviral, anti-inflammatory, antimicrobial and anticancer. They have been reported to possess inhibitory effects on calcium (Ca2+)/potassium (K+) channel, angiotensin-converting enzyme (ACE),
acyl-coenzyme A, thromboxane (TXA2 and TXB2), etc. Their excellent antiinflammatory actions were proposed to be due to their inhibition of different targets like lipooxygenase (LOX), cyclooxygenase (COX), interleukins (ILs), nitric oxide synthase and prostaglandins (PGs).
A review by Elkhalifa et al., (2020) on chalcone’s activities on the following human viruses: Middle East respiratory syndrome coronavirus, severe acute respiratory syndrome coronavirus, human immunodeficiency, influenza, human rhinovirus, herpes simplex, dengue, human cytomegalovirus, hepatitis B and C, Rift Valley fever and Venezuelan equine encephalitis.
Cardiovascular. 4-hydroxyderricin, one of the chalcones in the A. keiskei extract,
suppressed the elevation of systolic blood pressure (SBP) and induced a reduction in serum VLDL owing to a decrease in hepatic MTP mRNA expression in stroke-prone spontaneously hypertensive rats (SHRSP). Furthermore, 4-hydroxyderricin induced a decrease in hepatic FAS mRNA expression mediated by a decrease in hepatic ADD1 mRNA expression, resulting in a decrease in hepatic triglyceride content in SHRSP. These results indicate that 4-hydroxyderricin may be expected to exert a beneficial effect
on the prevention of atherosclerosis and suppression of hepatic lipid accumulation through improvement of lipid metabolism.
Glycyrrhizin (GL) was shown to inhibit SARS-coronavirus (SARS-CoV) replication in vitro. Amides of GL and conjugates of GL with two amino acid residues and a free 30-COOH function presented up to 70-fold increased activity against SARS-CoV but also increased cytotoxicity resulting in decreased selectivity index.38 System biology tools were applied to explore the potential of GL in modulating targets and pathways relevant to immune and inflammation responses. Which has the potential to regulate innate immune response by acting on NOD-like and Toll-like signaling pathways to promote interferons production, activate
and balance T-cells, and regulate the inflammatory response by inhibiting PI3K/AKT,
NF-B and MAPK signaling pathways. At low appropriate doses, GL has anti-inflammatory, anti-diabetic, antioxidant, anti-tumor, antimicrobial and anti-viral properties. A review by Ming & Yin (2013)
summarizes the effects of GL on metabolic syndrome, tumorigenesis, microbes and viruses, oxidative stress, and inflammation, as well as the reported side effects of the drug.40 GL can significantly inhibit the proliferation of HIV, showing an immune activation. The clinical application of GL on the prevention and treatments of various diseases may derive from its numerous pharmacological properties.
Because of the frequent mutations in the virus and its ability to cause cytokine storms, targeting the viral proteins has some drawbacks. Targeting cellular factors or pivotal inflammatory pathways triggered by SARSCoV-2 may produce a broader range of therapies. GL might be beneficial against SARS-CoV-2 because of its anti-inflammatory and antiviral characteristics and possible ability to regulate crucial host factors. Pathway enrichment analysis showed that the IL-17, IL-6, TNF-a, IFN signals, complement system, and growth factor receptor signaling are the main pathways. The interactions of TF genes and miRNA with com-
mon targets and the activity of TFs were also recognized. GL may inhibit COVID-19 through its anti-oxidant, anti-viral, and anti-inflammatory effects, and its ability to activate the immune system, and targeted therapy for those pathways is a predominant strategy to inhibit the cytokine storms triggered by SARS-CoV-2 infection.
Cardiovascular. Glycyrrhizin (glycyrrhizic acid) possess antioxidant properties in myocardium and protects against isoproterenol-induced oxidative stress. The most important protective mechanism offered
by glycyrrhizic acid is through its ability to decrease lipid hydroperoxides and isoprostanes and to increase the superoxide
dismutase and glutathione level. Thus, glycyrrhizic acid has been shown to possess cardioprotective effect against isoproterenol-induced acute myocardial infarction in rats.
An excessive infiltration of pro-inflammatory cells, mainly involving macrophages and T-helper 17 cells, has been found in lung tissues of patients with COVID-19 by post-mortem examination. Recently, increasing studies indicate that the "cytokine storm" may contribute to the mortality of COVID-19.46 In patients with mild-to-moderate COVID-19, the time to reach undetectable SARS-CoV2 was significantly shorter in the ART group than that in the control group.
Artemisinin can physically bind SARS-CoV-2 spike glycoproteins (6VXX and 6VYB), SARS-CoV-2 B.1.351 South Africa variant of Spike glycoprotein (7NXA), and even with ACE2 and prevent the SARS-CoV-2 binding to the host ACE2, TMPRSS2 and neutrapilin-1 receptors. Emodin showed best interac-
ulation showed that artemisinin has more stable interaction with 6VYB as compared to 6VXX, and hence proposed as potential phytochemical to prevent SARS-CoV-2 interaction with ACE-2 receptor.
He et al., (2021) consider the potential of molecular farming to address the challenges of endemic and re-emerging diseases, focusing on edible plants for the development of oral drugs. Key recent developments in this field include successful clinical trials based on orally delivered dried leaves of Artemisia annua against malarial parasite strains resistant to artemisinin combination therapy, the ability to produce clinical-grade protein drugs in leaves to treat infectious diseases and the long-term storage of protein drugs in dried leaves at ambient temperatures.
Results showed that baicalein inhibited cell damage induced by SARS-CoV-2 and improved the morphology of Vero E6 cells at a concentration of 0.1 M and above. Baicalein significantly inhibited the body weight loss, the replication of the virus, and relieved the lesions of lung tissue in hACE2 transgenic mice infected with SARS-CoV-2. In LPS-induced acute lung injury of mice, baicalein improved the respiratory function, inhibited inflammatory cell infiltration in the lung, and decreased the levels of IL-1B and TNF-a in serum.
Song et al., (2021) studied the anti-SARSCoV-2 activity of S. and its ingredients. They found that the ethanol extract of S. baicalensis and its major component, baicalein, inhibit SARS-CoV2 3CLpro activity and decreased the levels of IL-1B and TNF-a in serum. In conclusion, oral administration of crystal form B of baicalein could reach its effective concentration against SARSCoV-2. Baicalein could inhibit SARS-CoV-2-induced injury both in vitro and in vivo.
Baicalein inhibits amplification of VSV genome RNA and expression of VSV glycoprotein G (VSV-G) at comparable IC50s indicating this small molecule might not target certain step of viral life cycle, but more likely interferes a virus-host interaction.
Cardiovascular. In a study on ischemia/reperfusion (I/R) injury, Baicalein protects cardiomyocytes against I/R injury by oxidant scavenging and activation of the Akt-NOS-NO signaling.
Baicalein improved cardiac function and prevented LV hypertrophy. Second, they showed that baicalein inhibited the cardiac fibrosis. Third, it was found that baicalein strongly prevented the apoptosis of cardiac cells. Finally, baicalein modulated the activation and expression of Ca2 + handling proteins.
Based on recent laboratory and epidemiological studies, a growing list of mutations in the virus has the potential to enhance its transmission or help it evade the immune response. discuss the potential role
of Crocus sativus, (saffron) during and after COVID-19 infection, focusing on immunomodulation, respiratory, renal, and cardiovascular functions.
As a nutraceutical or drug supplement, it can alleviate the magnitude of COVID-19 symptoms in patients. The anti-inflammatory, antioxidant, and other medicinal properties attributed to saffron bioactive compounds can help in both pre-and post-infection management strategies.
The abnormalities associated with COVID-19 survivors include anxiety, depression, sleep disturbances, and post-traumatic stress disorder. Saffron can help manage these post-hospitalization abnormalities (subacute and chronic) too, owing to its anti-depressant property.
Saffron could help alleviate the symptoms of SARS-CoV-2 infection considering its pathophysiology, making it a suitable candidate as a drug supplement. The purpose is not to present saffron as a solution to COVID-19, but only to explore its use in the integrated management of COVID-19.
Stress. The typical stress-induced decrease in heart rate variability (HRV) during exposure to the stressor was attenuated following acute saffron intake. Saffron extract appears to improve subclinical depressive symptoms in healthy individuals and may contribute to increased resilience against the development of stress-related psychiatric disorders.
Fatigue. In this study Saffron treatment on endurance capacity, mitochondrial biogenesis, inflammation, antioxidant, and metabolic biomarkers was analyzed. They showed that the saffron extract treatment during endurance training could improve endurance capacity by modulating several metabolic and genomic factors.
The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.
Symptoms in multisystem inflammatory syndrome (MIA-C) typically occur 4-6 weeks after infection and the disease is characterized by elevated markers of inflammation and the presence of multiple
autoantibodies autoimmune and inflammatory diseases are now increasingly identified following COVID-19. The etiology of MIA remains unknown. autoimmune and inflammatory diseases are now increasingly identified following COVID-19. The etiology of MIA remains unknown. More than 50% of patients on or following chemotherapy develop symptoms similar to those described above for long-COVID syndrome especially cognitive dysfunction a condition that has been termed "chemofog" or "chemobrain," and has been associated with distinct neuroimaging findings.
SARS-CoV-2 could enter the brain via the
olfactory nerve tract reaching the hypothalamus where it could activate brain mast cells and microglia to release pro-inflammatory molecules, thus contributing to brain inflammation and brain fog. mast cells could be inhibited with the structurally related natural flavonoids luteolin and quercetin, which are readily available and are generally considered safe. Both flavonoids have broad anti-viral properties, inhibit entry of the virus into host cells, inhibit neuroinflammation and reduce cognitive decline. Furthermore, luteolin better penetrates
into the brain, inhibits both microglia and mast cells, and has been reported to reduce neuroinflammation and cognitive dysfunction.
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